A substantial number of studies strongly indicate that the viral envelope gene (env) determines the cell specificity of HIV-1 and suggest that the cell specificity of human immunodeficiency virus type 1 (HIV-1) is one of the keys to understanding the complex nature of disease processes in AIDS. HIV-1, with its high replicative ability for macrophages, may have an important role in the transmission and persistence of HIV-1, and T-lymphocytes may be responsible for the clinical manifestation of immunodeficiency. The molecular mechanisms by which cell type-specific HIV-1 influences the disease course and disease manifestation, however, remain to be elucidated. We explored the significance of viral cell specificity for the disease processes of AIDS using the simian immunodeficiency virus (SIV)/rhesus macaque model system. An SIVmac155/TT variant with high replicative and cytopathic ability for rhesus T-lymphocytes from the lymph nodes of a rhesus macaque that died following infection with cloned SIVmac239 was isolated. An SIVmac155/MT variant with high replicative ability for macrophages from the lymph nodes of the same individual was also isolated. Sequence analysis revealed variant specific amino acid changes in the V1 to V2 and V3 regions of gp120. Ev/T3 env recombinant containing the TT-derived gp120 sequences and Ev/M3 env recombinant containing the MT-derived gp120 sequences displayed strong replicative ability for T-lymphocytes and macrophages, respectively. Sequence analysis revealed TT-type env variant was specifically present in the lymph nodes, but MT type env variants were present in the lymph nodes and brain of the animal. These data suggest that the gp120 of SIV is not only important for determining the cell specificity, but may also contribute to SIV tissue localization in vivo. The significance of gp120 sequences of SIV for viral pathogenicity in vivo was examined by experimental inoculation of four rhesus macaques with either Ev/T3 or SIVmac239. All macaques established virus infection as determined by plasma SIV antigenemia and anti-SIV antibody responses. Surprisingly, all four macaques infected by Ev/T3 displayed very rapid, severe and selective depletion of CD4+ T cells in peripheral blood at 2 weeks post-inoculation. In contrast, no macaques infected by SIVmac239 displayed CD4+ T cell depletion through the course of infection. The CD4/CD8 ratio in lymph nodes was also severely inverted in macaques infected with Ev/T3, but not SIVmac239. These studies demonstrated that the high replicative and cytopathic abilities of Ev/T3 in CD4+ T cells in vitro remarkably reflect the potential of this cloned virus to induce CD4+ T cell depletion in vivo.